U.S. patent application number 11/662833 was filed with the patent office on 2008-10-23 for highly-aqueous, non-respirable aerosols containing biologically-active ingredients, method of making, and device therefor.
This patent application is currently assigned to Battelle Memorial Institute. Invention is credited to Sreedhara Alavattam, Ada S. Cowan, James E. Dvorsky, William M. Fountain, Beverly A. Piatt, Mark R. Wilson.
Application Number | 20080259519 11/662833 |
Document ID | / |
Family ID | 35708696 |
Filed Date | 2008-10-23 |
United States Patent
Application |
20080259519 |
Kind Code |
A1 |
Cowan; Ada S. ; et
al. |
October 23, 2008 |
Highly-Aqueous, Non-Respirable Aerosols Containing
Biologically-Active Ingredients, Method of Making, and Device
Therefor
Abstract
A non-respirable aerosol, particularly a non-respirable aerosol
comprising a biologically-effective amount of a biologically-active
agent dissolved, emulsified, or suspended in a highly-aqueous
liquid carrier vehicle. The highly-aqueous liquid carrier vehicle
comprises about 60 wt % to about 100 wt % water, about 0 wt % to
about 40 wt % of a co-solvent, about 0.05 wt % to about 10 wt % of
an acceptable surfactant, and about 0 wt % to about 10 wt % of an
excipient. The non-respirable aerosol is substantially monodisperse
when dispensed from a sprayhead assembly comprising a preferably
linear array of a plurality of nozzles and at least one counter
electrode adapted to substantially equalize the charge fields of
the plurality of nozzles.
Inventors: |
Cowan; Ada S.; (Lewis
Center, OH) ; Alavattam; Sreedhara; (Fremont, CA)
; Piatt; Beverly A.; (Columbus, OH) ; Dvorsky;
James E.; (Norwich Township, OH) ; Fountain; William
M.; (Circleville, OH) ; Wilson; Mark R.;
(Columbus, OH) |
Correspondence
Address: |
BATTELLE MEMORIAL INSTITUTE
505 KING AVENUE
COLUMBUS
OH
43201-2693
US
|
Assignee: |
Battelle Memorial Institute
Columbus
OH
|
Family ID: |
35708696 |
Appl. No.: |
11/662833 |
Filed: |
September 14, 2005 |
PCT Filed: |
September 14, 2005 |
PCT NO: |
PCT/US05/33108 |
371 Date: |
February 7, 2008 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60609791 |
Sep 14, 2004 |
|
|
|
Current U.S.
Class: |
361/228 ;
504/362; 514/772 |
Current CPC
Class: |
B05B 1/14 20130101; B05B
5/0533 20130101; A01N 25/06 20130101; A61K 9/12 20130101; A01N
25/30 20130101; A01N 25/02 20130101; A01N 39/02 20130101; A01N
37/40 20130101; A01N 39/04 20130101; B05B 5/0535 20130101; A01N
25/06 20130101 |
Class at
Publication: |
361/228 ;
514/772; 504/362 |
International
Class: |
B05B 5/053 20060101
B05B005/053; A01N 25/06 20060101 A01N025/06; A01P 1/00 20060101
A01P001/00; A01P 3/00 20060101 A01P003/00; A01P 13/00 20060101
A01P013/00; A01P 15/00 20060101 A01P015/00; A01P 21/00 20060101
A01P021/00 |
Foreign Application Data
Date |
Code |
Application Number |
Jul 7, 2005 |
US |
10/541681 |
Claims
1. An aqueous liquid carrier vehicle for direct delivery of an
aerosol having a particle size of between about 60 .mu.m to about
800 .mu.m, the liquid carrier vehicle comprising: about 60 wt % to
about 100 wt % water; about 0 wt % to about 40 wt % of a
co-solvent; about 0.05 wt % to about 10 wt % of an acceptable
surfactant; and about 0 wt % to about 10 wt % of an excipient;
wherein: the aerosol is produced using EHD means; and the liquid
carrier vehicle has a resistivity of about 0.05 ohm-m to about 100
ohm-m, a surface tension of about 20 dynes/cm to about 72 dynes/cm,
and a viscosity of about 0.1 cPs to about 100 cPs.
2. The liquid carrier vehicle of claim 1, wherein: the particles
have a GSD of less than about 1.65.
3. The liquid carrier vehicle of claim 1, wherein: the liquid
carrier vehicle contains about 70 wt % to about 99 wt % water.
4. The liquid carrier vehicle of claim 3, wherein: the liquid
carrier vehicle contains about 90 wt % to about 95 wt % water.
5. The liquid carrier vehicle of claim 1, wherein: the liquid
carrier vehicle contains about 5 wt % to about 10 wt % of the
co-solvent.
6. The liquid carrier vehicle of claim 1, wherein: the liquid
carrier vehicle contains about 99 wt % water and about 1 wt % of
the co-solvent.
7. The liquid carrier vehicle of claim 1, wherein: the co-solvent
has a surface tension of about 30 dynes/cm or less.
8. The liquid carrier vehicle of claim 1, wherein: the co-solvent
is selected from the group consisting essentially of: ethanol,
2-ethylhexanol, diacetone alcohol, diisobutyl ketone, isobutanol,
isophorone, methyl isobutyl ketone, n-butanol, n-pentanol,
n-propanol, polyalcohols, propylene glycol, polyethylene glycol,
glycerol, and combinations thereof.
9. The liquid carrier vehicle of claim 8, wherein: the co-solvent
is ethanol.
10. The liquid carrier vehicle of claim 1, wherein: the liquid
carrier vehicle contains about 0.05 wt % to about 5 wt % of the
surfactant.
11. The liquid carrier vehicle of claim 10, wherein: the liquid
carrier vehicle contains about 0.1 wt % to about 2.5 wt % of the
surfactant.
12. The liquid carrier vehicle of claim 11, wherein: the liquid
carrier vehicle contains about 1 wt % of the surfactant.
13. The liquid carrier vehicle of claim 1, wherein: the surfactant
is selected from the group consisting essentially of: glycosides,
polyoxyethylene ethers, alkyl-.beta.-D-glucopyranosides,
polyoxyethylene 10 tridecyl ether, ethoxylated iso-decyl alcohol,
and alkyl-.beta.-D-maltoglucopyranosides.
14. The liquid carrier vehicle of claim 1, wherein: the particle
size is between about 100 .mu.m to about 500 .mu.m.
15. The liquid carrier vehicle of claim 14, wherein: the particle
size is between about 150 .mu.m to about 200 .mu.m.
16. The liquid carrier vehicle of claim 1, wherein the liquid
carrier vehicle comprises: about 95 wt % to about 100 wt % water;
about 0 wt % to about 5 wt % of the co-solvent; about 0.1 wt % to
about 2.5 wt % of the surfactant; and about 0.1 wt % to about 2.5
wt % of the excipient; and wherein: the liquid carrier vehicle has
a resistivity of about 0.1 ohm-m to about 100 ohm-m; a viscosity of
about 1 cPs to about 40 cPs; and a surface tension of about 20
dynes/cm to about 50 dynes/cm.
17. The liquid carrier vehicle of claim 16, wherein: the liquid
carrier vehicle has a resistivity of about 0.25 ohm-m to about 5
ohm-m; a viscosity of about 1.5 cPs to about 40 cPs; and a surface
tension of about 20 dynes/cm to about 40 dynes/cm.
18. An aerosol having a particle size of between about 60 .mu.m to
about 800 .mu.m, and comprising: a biologically-effective amount of
a biologically-active agent dissolved, suspended, or emulsified in
the aqueous liquid carrier vehicle of claim 1.
19. The aerosol of claim 18, wherein: the concentration of the
biologically-active agent is about 0.1 wt % to about 30 wt %.
20. The aerosol of claim 19, wherein: the biologically-active agent
is selected from the group consisting essentially of: herbicides,
plant growth regulators, insecticides, fungicides, miticides,
biocides, antibacterials, antivirials, topical antihistamines,
ocular decongestants, and disinfectants.
21. The aerosol of claim 18, wherein: the liquid carrier vehicle
contains about 70 wt % to about 99 wt % water.
22. The aerosol of claim 21, wherein: the liquid carrier vehicle
contains about 85 wt % to about 95 wt % water.
23. The aerosol of claim 21, wherein: the liquid carrier vehicle
contains about 1 wt % to about 30 wt % of the co-solvent.
24. The aerosol of claim 23, wherein: the liquid carrier vehicle
contains about 5 wt % to about 15 wt % of the co-solvent.
25. The aerosol of claim 18, wherein: the co-solvent is selected
form the group consisting of ethanol, 2-ethylhexanol, diacetone
alcohol, diisobutyl ketone, isobutanol, isophorone, methyl isobutyl
ketone, n-butanol, n-pentanol, n-propanol, and combinations
thereof.
26. The aerosol of claim 25, wherein: the co-solvent is
ethanol.
27. The aerosol of claim 18, wherein: the liquid carrier vehicle
contains about 0.05 wt % to about 5 wt % of the surfactant.
28. The aerosol of claim 27, wherein: the liquid carrier vehicle
contains about 0.1 wt % to about 2.5 wt % of the surfactant.
29. The aerosol of claim 28, wherein: the liquid carrier vehicle
contains about 1 wt % of the surfactant.
30. The aerosol of claim 18, wherein: the surfactant is selected
from the group consisting of alkyl polyglycosides, polyoxyethylene
ethers. alkyl-.beta.-D-glucopyranosides and
alkyl-.beta.-D-maltoglucopyranosides.
31. The aerosol of claim 18, wherein: the particle size is between
about 100 .mu.m to about 500 .mu.m.
32. The aerosol of claim 31, wherein: the particle size is between
about 150 .mu.m to about 250 .mu.m .
33. The aerosol of claim 18, wherein: the liquid carrier vehicle
has a resistivity of about 0.1 ohm-m to about 10 ohm-m; a viscosity
of about 1 cPs to about 50 cPs; and a surface tension of about 20
dynes/cm to about 50 dynes/cm.
34. The aerosol of claim 33 wherein: the liquid carrier vehicle has
a resistivity of about 0.25 ohm-m to about 5 ohm-m; a viscosity of
about 1.5 cPs to about 40 cPs; and a surface tension of from abut
20 dynes/cm to about 40 dynes/cm.
35. A method for delivering a biologically-active agent to a target
surface in need treatment, comprising the steps of: a. preparing an
aqueous liquid carrier vehicle according to claim 1; b. dissolving,
suspending, or emulsifying a biologically-effective amount of the
biologically-active agent in the liquid carrier vehicle; c.
producing an aerosol of the solution or suspension using EHD means,
wherein: the aerosol particle size is about 60 .mu.m to about 800
.mu.m; and d. applying the aerosol to the target surface.
36. The method of claim 35, wherein: the concentration of the
biologically-active agent in the liquid carrier vehicle is about
0.1 wt % to about 30 wt %.
37. The method of claim 36, wherein: the biologically-active agent
is selected from the group consisting essentially of herbicides,
plant growth regulators, insecticides, fungicides, miticides,
biocides, antibacterials, antivirials, topical antihistamines,
ocular decongestants, and disinfecting agents.
38. The method of claim 35, wherein: the liquid carrier vehicle
contains about 70 wt % to about 99 wt % water.
39. The method of claim 38, wherein: the liquid carrier vehicle
contains about 85 wt % to about 95 wt % water.
40. The method of claim 38, wherein: the liquid carrier vehicle
contains about 1 wt % to about 30 wt % of the co-solvent.
41. The method of claim 40, wherein: the liquid carrier vehicle
contains about 5 wt % to about 15 wt % of the co-solvent.
42. The method of claim 35, wherein: the co-solvent is selected
from the group consisting of ethanol, 2-ethylhexanol, diacetone
alcohol, diisobutyl ketone, isobutanol, isophorone, methyl isobutyl
ketone, n-butanol, n-pentanol, n-propanol, and combinations
thereof.
43. The method of claim 42 wherein the co-solvent is ethanol.
44. The method of claim 35, wherein: the liquid carrier vehicle
contains about 0.05 wt % to about 5 wt % of the surfactant.
45. The method of claim 44, wherein: the liquid carrier vehicle
contains about 0.1 wt % to about 2.5 wt % of the surfactant.
46. The method of claim 45, wherein: the liquid carrier vehicle
contains about 1 wt % of the surfactant.
47. The method of claim 35, wherein: the surfactant is selected
from the group consisting of alkyl polyglycosides, polyoxyethylene
ethers, alkyl-.beta.-D-glucopyranosides, and
alkyl-.beta.-D-maltoglucopyranosides.
48. The method of claim 35, wherein: the aerosol particle size is
about 80 .mu.m to about 500 .mu.m.
49. The method of claim 35, wherein: the liquid carrier vehicle has
a resistivity of about 2.5 ohm-m to about 5 ohm-m; a viscosity of
about 1.5 cPs to about 40 cPs; and a surface tension of about 20
dynes/cm to about 40 dynes/cm.
50. A method for delivering a biologically-active agent to a target
surface in need treatment, comprising the steps of: a. providing a
biologically-effective amount of the biologically-active agent
dissolved, emulsified, or suspended in a liquid carrier vehicle
according to claim 1; b. providing a device according to claim 51;
c. introducing the liquid carrier vehicle containing the agent into
the reservoir; d. producing an aerosol of the solution or
suspension using EHD means, wherein: the aerosol particle size is
about 60 .mu.m to about 800 .mu.m; and f. applying the aerosol to
the target surface.
51. A device for producing an aerosol, the device comprising: a
source of a liquid to be aerosolized; a nozzle array in liquid
communication with the source, the nozzle array comprising: a
plurality of nozzles, the plurality of nozzles comprising: at least
one inner nozzle; and at least one first and at least one second
outer nozzle; an electrical charger, the charger in electrical
communication with the liquid or the nozzle array; at least one
counter electrode in charge communication with the liquid or the
nozzle array, the counter electrode comprising: a first end; and a
second end; wherein: the first end is aligned with, or positioned
inboard of, the at least first outer nozzle; the second end is
aligned with, or positioned inboard of, the at least second outer
nozzle; wherein: the liquid or the nozzle array is at a different
potential than the counter electrode.
52. The device of claim 51, wherein: the plurality of nozzles is
configured in a substantially linear arrangement.
53. A device for producing an aerosol, the device comprising: a
source of a liquid to be aerosolized; a nozzle array in liquid
communication with the source, the nozzle array comprising: a
plurality of nozzles, the plurality of nozzles comprising: at least
one inner nozzle; and at least one first and at least one second
outer nozzle; an electrical charger, the charger in electrical
communication with the liquid or the nozzle array; at least one
counter electrode, the counter electrode in charge communication
with the nozzle array and comprising: a first end portion; a second
end portion; and a central portion therebetween; wherein: the
central portion is positioned closer to at least one inner nozzle
than the first end portion is positioned to a first outer nozzle,
and the central portion is positioned closer to at least one inner
nozzle than the second end portion is positioned to a second outer
nozzle; and wherein: the liquid or the nozzle array is at a
different potential than the counter electrode.
54. The device of claim 53, wherein: the plurality of nozzles is
configured in a substantially linear arrangement.
55. The device of claim 53, wherein: the counter electrode
comprises a series of discrete electrodes.
56. The device of claim 55, wherein: the discrete electrodes are
aligned in a curvilinear pattern.
57. The device of claim 53, wherein: at least the first end portion
of the counter electrode is substantially curved away from at least
the first outer nozzle.
58. The device of claim 53, wherein: the counter electrode central
portion is curved.
59. The device of claim 53, wherein: the counter electrode central
portion is substantially linear.
60. A sprayhead assembly for EHD spraying, the assembly comprising:
a nozzle array, the nozzle array comprising: a plurality of
nozzles, the plurality of nozzles comprising: at least one inner
nozzle; and at least a first and at least a second outer nozzle; at
least one counter electrode, the counter electrode in charge
communication with the nozzle array and comprising: a first end
portion; a second end portion; and a central portion therebetween;
wherein: the central portion is positioned closer to at least one
inner nozzle than the first end portion is positioned to a first
outer nozzle, and the central portion is positioned closer to at
least one inner nozzle than the second end portion is positioned to
a second outer nozzle; and wherein: the liquid or the nozzle array
is at a different potential than the counter electrode.
61. The sprayhead assembly of claim 60, wherein: the plurality of
nozzles is configured in a substantially linear arrangement.
62. The sprayhead assembly of claim 60, wherein: the counter
electrode comprises a continuous filament.
63. A sprayhead assembly for EHD spraying, the assembly comprising:
a substantially linear counter electrode; a nozzle array, the
nozzle array in charge communication with the counter electrode,
and comprising: a plurality of nozzles, the plurality of nozzles
comprising: at least one central nozzle; and at least a first and
at least a second outer nozzle; wherein: a central nozzle is
positioned closer to the counter electrode than a first outer
nozzle is positioned to the counter electrode and a central nozzle
is positioned closer to the counter electrode than a second outer
nozzle is positioned to the counter electrode.
64. A sprayhead assembly for EHD spraying, the assembly comprising:
a nozzle array, the nozzle array comprising: a plurality of
nozzles, the plurality of nozzles comprising: at least one central
nozzle; and at least a first and at least a second outer nozzle;
and a plurality of counter electrodes; wherein: the field intensity
of the at least one central nozzle is substantially the same as the
field intensity of the at least first and at least second outer
nozzle.
65. A sprayhead assembly for EHD spraying, the assembly comprising:
a nozzle array, the nozzle array comprising: a plurality of
nozzles, the plurality of nozzles configured in a substantially
linear arrangement and comprising: at least one central nozzle; and
at least a first and at least a second outer nozzle; and at least a
first, a second, and a third counter electrode; wherein: the at
least one central nozzle is positioned closer to the at least first
counter electrode than the at least first outer nozzle is
positioned to the second counter and than the at least second outer
nozzle is to the third counter electrode.
66. A method of producing an aerosol, the method comprising the
steps of: a. providing a liquid to be aerosolized; b. providing a
nozzle array, the nozzle array comprising: a plurality of nozzles,
the plurality of nozzles configured in a substantially linear
arrangement; c. providing a plurality of counter electrodes; d.
applying a charge to the liquid or to each of the plurality of
nozzles; e. substantially equalizing the field intensity
experienced by each of the plurality of nozzles.
67. The method of claim 66, wherein: the aerosol has a GSD of
between about 1.10 and 1.65.
68. The method of claim 66, wherein: the aerosol is substantially
monodisperse.
69. The method of claim 66, wherein: the liquid is comprises the
liquid carrier vehicle of claim 1.
70. A method of substantially equalizing the fields about a
plurality of nozzles, the method comprising the steps of: a.
providing a plurality of nozzles; b. charging at least two of the
plurality of nozzles, wherein the charge on the at least two
nozzles is unequal; c. providing at least one counter electrode; d.
applying a charge or ground to the at least one counter electrode,
whereby the field on the at least two nozzles becomes substantially
equal.
Description
CROSS-REFERENCE TO RELATED APPLICATION(S)
[0001] This Application claims priority to i) Provisional U.S. Pat.
App. No. 60/609,791, filed Sep. 14, 2004, and ii) Int'l App. No.
PCT/US2004/000556, U.S. patent application Ser. No. 10/541,681, now
U.S. Pat. No. ______, which claims priority to Provisional U.S.
Pat. App. Nos. i) 60/439,254, filed Jan. 10, 2003, now abandoned,
ii) 60/439,257, filed Jan. 10, 2003, now abandoned, and iii)
60/439,606, filed Jan. 11, 2003, now abandoned, the contents of
which are incorporated herein by reference as if fully rewritten
herein.
STATEMENT REGARDING FEDERALLY-SPONSORED RESEARCH OR DEVELOPMENT
[0002] Not applicable.
INCORPORATION-BY-REFERENCE OF MATERIAL SUBMITTED ON A CD
Not applicable.
BACKGROUND OF THE INVENTION
[0003] 1. Field of the Invention
[0004] The present invention relates to the field of non-respirable
aerosols, particularly non-respirable aerosols produced from very
low-resistivity liquid compositions, particularly very
low-resistivity aqueous liquid compositions, using
electrohydrodynamic (EHD) means, including an improved nozzle, for
generating small, uniform, non-respirable aerosol particles
comprising biologically-active agents, as well as to methods of
using such liquid formulations to deliver biologically-active
agents to a target surface.
[0005] 2. Description of Related Art
[0006] Creating non-respirable particles of highly-aqueous liquid
formulations using EHD presents some unique problems. To effect the
Taylor cone, which is the hallmark of EHD, the liquid must be
subjected to a charge sufficient to overcome the surface tension of
the liquid and the liquid breaks apart (a process called
comminution). In a highly-aqueous formulation, the surface tension
which must be overcome is generally very high. In addition, the
resistivity of the formulation is very low which inhibits formation
of a charge on the liquid and the formation of the Taylor cone. To
overcome the surface tension in a highly-aqueous, high-resistivity
formulation, a high charge is required. This, in turn, creates
particles of very small size, at very low delivery rates, and
generally non-uniform dispersions. Thus, there is a need to create
larger, non-respirable particles of highly-aqueous,
high-resistivity formulations that can be utilized in situations
where respiration would be harmful.
[0007] Handheld electrohydrodynamic aerosolization/spraying means
are known in the art. U.S. Pat. No. 6,397,838 to Zimlich et al.
describes a handheld, EHD pulmonary aerosol delivery device that
produces a cloud of aerosolized liquid particles having a
mono-disperse, respirable particle size and mean zero velocity. As
described in Zimlich, the aerosol particles are such that at least
about 80 percent have a diameter of less than or equal to about 5
microns.
[0008] U.S. Pat. No. 4,381,533 to Coffee describes an EHD spray
device, principally for use in crop spraying. A stated essential
component of the Coffee spray device is a circular field
intensifying electrode, sited annularly adjacent to the circular
sprayhead. In use, it is stated to reduce the incidence of corona
discharge which interferes with spray production and thereby allows
lower electric field strengths to be used during spray
generation.
[0009] U.S. Pat. No. 6,503,481 to Thurston et al. teaches a method
for delivering a biologically-active material to the respiratory
tract of a patient in need of treatment comprising the steps of
producing a respirable aerosol of a liquid composition using an EHD
spraying means and administering the aerosol to the pulmonary tract
of a patient via inhalation of the aerosol. The aerosol comprises a
pharmaceutically-effective amount of an active agent in a carrier
liquid in which the active agent is dissolved, emulsified, or
suspended. Specific liquid medicament formulations are described
which are useful in the methods of the invention.
[0010] Various liquid medicament formulations suitable for
aerosolization using an EHD device and administration to a patient
by pulmonary delivery are described in the following U.S. Pat. Pub.
Nos. 2002/0102218 to Cowan and 2002/0110524 and 2003/0185762 to
Cowan et al. None of these publications disclose the particular
non-respirable aerosols described and claimed herein.
[0011] Finally, especially with multiple-nozzle arrays, and
particularly with multiple-nozzle arrays that are substantially
linear, the field intensity at each nozzle, or spray site, varies
from site to site due to the effect each nozzle has on adjacent
nozzles. Such uneven field intensity results in uneven
aerosolization and uneven particle size, which, in turn, results in
a much greater particle size distribution. This interferes with the
spraying of aqueous formulations using multiple nozzle arrays, and
particle size variability can also be undesirable when spraying
biologically-active materials.
[0012] There is, therefore, a need for improved highly-aqueous
non-respirable aerosols, methods of making same, and devices
therefor.
BRIEF SUMMARY OF THE INVENTION
[0013] The invention is directed to non-respirable aerosols useful
for delivery of a biologically-active agent to a target surface, as
well as to methods of treating a target surface using such
biologically-active aerosols, and further to highly-aqueous liquid
carrier vehicles for biologically-active agents which are suitable
for aerosolization using an EHD spraying means. An improved
sprayhead assembly for generating such aerosols is also
disclosed.
[0014] One object of the present invention is to provide an aqueous
liquid carrier vehicle for direct delivery of an aerosol having a
particle size of between about 60 .mu.m and about 800 .mu.m and
containing a dissolved or suspended optionally biologically-active
agent, comprising about 60 weight percent to about 100 weight
percent water, about zero weight percent to about 40 weight percent
co-solvent, about 0.05 weight percent to about 10 weight percent of
an acceptable surfactant, and about zero weight percent to about 10
weight percent of an optionally biologically-acceptable excipient,
wherein the liquid carrier vehicle has a resistivity of about 0.05
ohm-m to about 20 ohm-m, a surface tension of about 20 dynes/cm to
about 100 dynes/cm, and a viscosity of about 0.1 cPs to about 100
cPs.
[0015] It is a further object of the present invention to provide
an aqueous liquid carrier vehicle for direct delivery of an aerosol
having particles having a GSD of about 1.10 to about 1.65.
[0016] It is a further object of the present invention to provide
an aqueous liquid carrier vehicle comprising a surfactant having a
surface tension of about 30 dynes/cm or less.
[0017] Another object of the present invention is to provide an
aerosol, using EHD means, having a particle size between about 60
.mu.m and about 800 .mu.m and comprising a biologically-effective
amount of a biologically-active agent dissolved, suspended, or
emulsified in the aqueous liquid carrier vehicle described herein
above.
[0018] Yet another object of the present invention is to provide a
method for delivering a biologically-active agent to a target
surface in need of treatment, comprising the steps of preparing an
aqueous liquid carrier vehicle as described herein above,
dissolving, suspending, or emulsifying a biologically-effective
amount of the biologically-active agent in the liquid carrier
vehicle, producing an aerosol of the solution or suspension using
EHD means, wherein the aerosol particle size in about 60 .mu.m to
about 800 .mu.m and applying the aerosol to the target surface.
[0019] Yet another object of the present invention is to provide a
sprayhead assembly for EHD spraying, comprising a nozzle array, the
nozzle array comprising a plurality of nozzles, preferably
configured in a substantially linear arrangement, and comprising at
least one, preferably a plurality or array, of inner nozzles and
preferably at least one first and at least one second nozzle (also
referred to herein as a first array and a second array of outer
nozzles, respectively), at least one field-equalizing counter
electrode, the counter electrode in charge communication with the
nozzle array and comprising a first end portion, a second end
portion, and a central portion therebetween, wherein the central
portion is positioned closer to the array of inner nozzles than the
first end portion is positioned to the first array of outer nozzles
and than the second end portion is positioned to the second array
of outer nozzles.
[0020] It is yet another object of the present invention to provide
a method of substantially equalizing the fields about a plurality
of nozzles, the method comprising the steps of providing a
plurality of nozzles, charging at least two of the plurality of
nozzles, wherein the charge on the at least two nozzles in unequal,
providing at least one counter electrode, and applying a charge or
ground to the at least one counter electrode, whereby the field on
the at least two nozzles becomes substantially equal.
[0021] In EHD practice, as described hereinabove, the liquid is
subject to a charge which causes it to form a Taylor cone and,
subsequently, to comminute. It is the charge on the liquid at the
Taylor cone that, in part, controls the comminution. An electrical
charger is placed in electrical communication with the liquid,
either directly via the fluid itself, or indirectly via the nozzle.
It is well within the ability of EHD spraying to provide a
substantially monodisperse aerosol when using one spray site. In
practice, however, a higher flowrate is often desired than is
practically achievable with a single site. In a multi-site nozzle
array, especially one that is substantially linear, the charge
experienced by the liquid in the Taylor cone may be affected by the
charge on nearby sites. Thus, not all sites (Taylor cones) will
produce the same aerosol distribution.
[0022] The present invention introduces a counter electrode design
that can alter the charge at each site by affecting the field at
the spray site in the vicinity of the Taylor cone in a manner which
alters, influences, and can make more equal or substantially equal,
the charge at each spray site, cause the collective aerosol to be
more monodisperse, and provide control of droplet size. This
ability of the counter electrode to effect the charge at the spray
sites without being in electrical contact with the spray site is
referred to herein as "charge communication".
[0023] It may be understood that not only may varying the shape and
charge of the counter electrode one may effect charge communication
with a series of spray sites, but also that such charge
communication can be adjusted on a given spray head mechanically or
electrically. Mechanical adjustment is possible by placing the
counter electrode of the present invention (whether a curved
filament or a series of individual counter electrodes) on
adjustable or movable supports which permit adjustment in the three
dimensions of height relative to the spray sites, distance of the
electrode to the spray sites, or curvature of the counter
electrode. Where a series of individual electrodes comprise the
counter electrode in accordance with the present invention, each of
the individual electrodes of the counter electrode may be
separately adjustable.
[0024] As well, electrical adjustment of the counter electrode of
the present invention alone or in combination with mechanical
adjustment features, permits controlled application of charge
communication to tune an apparatus as needed for spraying a
particular material, and to create desired dispersion
characteristics. To this end, the voltage on the counter electrode
can be changed as desired. Alternatively, the charge on ones of a
series of counter electrodes arranged in accordance with the
present invention can be separately controlled and thus dynamically
adjusted to vary the charge communication and influence spray site
performance. Electronic controllers may be useful in this regard to
provide dynamic adjustment during use.
BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS
[0025] The following detailed description of the embodiments of the
invention will be more readily understood when taken in conjunction
with the following drawing, wherein:
[0026] FIGS. 1-9 are plots of particle size data for the various
examples described herein.
[0027] FIGS. 10-12 illustrate a nozzle assembly according to an
aspect of the present invention.
[0028] FIGS. 13-21 illustrate various embodiments of a nozzle
assembly according to another aspect of the present invention.
[0029] FIGS. 22-51 picture FEA results of various embodiments of a
nozzle assembly according to another aspect of the present
invention.
DETAILED DESCRIPTION OF THE INVENTION
[0030] In one embodiment of the present invention, an aqueous
[0031] As used herein, the term "electrohydrodynamic" or "EHD" may
also be referred to as "electric field effect technology" or "EFET"
and these terms are used interchangeably. Dispensing devices are
known which produce a finely divided spray of liquid particles EFET
(EHD) means. These sprayers have found use in many areas,
including, without limitation, medicine for the administration of
medicaments and biologicals by topical application or inhalation,
in agriculture for crop spraying, in consumer markets for consumer
products, and in industry for spraying coatings, paints, and other
materials used in manufacturing processes.
[0032] The EHD spraying means described herein may be stationary or
handheld. Such devices are "stationary" in the respect that their
size prevents them from being easily held and carried by the user.
Stationary EHD devices may be portable if moved on a cart, dolly,
or vehicle such as a truck or an airplane. In many of the
applications described herein, it is advantageous that the EHD
device be small, portable, and handheld. As an example, an EHD
device about the size of a cell phone would enable the
user/applicator to use apply the biologically active aerosols in a
variety of locations where it would be inconvenient to move a
larger device. For example, a portable, handheld EHD device is
ideal for treating one's clothing in a wooded or field environment
where there may be deer ticks infected with the bacterium Borrelia
burgdorferi, which causes Lyme Disease and which is transmitted to
humans by the bite of an infected deer tick.
[0033] In a typical EHD device, a fluid delivery means delivers
fluid to be aerosolized to a nozzle and the fluid or the nozzle is
maintained at high electric potential. One type of nozzle used in
EHD devices is a capillary tube capable of conducting electricity.
An electric potential is placed on the capillary tube which charges
the fluid contents or upon the fluid itself such that, as the fluid
emerges from the tip or end of the capillary tube, a so-called
Taylor cone is formed. This cone shape results from a balance of
the forces of electric charge on the fluid and the surface tension
of the fluid Desirably, the charge on the fluid overcomes the
surface tension and at the tip of the Taylor cone, a thin jet of
fluid forms and subsequently and rapidly separates a short distance
beyond the tip into an aerosol. Studies have shown that the aerosol
from a single capillary nozzle can have a substantially uniform
particle size and a high velocity leaving the tip but that it
quickly decelerates to a very low velocity a short distance beyond
the tip.
[0034] EHD sprayers produce charged particles at the tip of the
nozzle. Depending upon the use, these charged particles can be
partially- or fully-neutralized (with, for example, a discharge
electrode in the sprayer device). When the EFET device is used to
deliver therapeutic, respirable aerosols, it is preferred that the
aerosol be completely electrically neutralized prior to inhalation
by the user to permit the aerosol to reach the pulmonary areas
where the particular therapeutic formulation is most effective. In
the case of a non-therapeutic, non-respirable aerosol such as the
subject of the present invention, typically the aerosol is intended
to be deposited on a target surface, and an EFET sprayer without
means for discharging or with means for only partially discharging
an aerosol might be preferred since the aerosol would have a
residual electric charge as it leaves the sprayer so that the
particles would be attracted to and tightly adhere to the target
surface.
[0035] The nozzle assembly of an EHD spray device may include one
or more, preferably two for a linear nozzle array, so-called
"dummy" electrodes. In practice, a dummy electrode is placed at
each end of the nozzle array. While the dummy electrodes are
charged similarly to the active spray sites, no fluid is supplied
to them. They serve only to help balance the electric charges,
especially at the outermost spray sites in a linear array. See,
e.g., U.S. Pat. No. 6,302,331 to Dvorsky et aL. cited above.
[0036] Int'l App. No. PCT/US2004/000556, to which the instant
application claims priority, the contents of which are included
herein by reference as if fully rewritten herein, discloses a
spray-shaping mechanism comprising parallel counter electrodes.
These counter electrodes may be employed in "localizing" the
electric field that is produced at the spray site. The counter
electrodes may effectively boost the velocity of the EHD spray
forward, as well as shape or split the spray toward a desired
target. This feature is capable of presenting a more uniform field
to each spray site. Alternatively, a counter electrode may be
referred to as a "reference" electrode. What is intended, however,
is that the electrode has a potential relative to the spray site.
As will be appreciated by those skilled in the art, no implication
is intended as to any specific polarity or relativity to earth
ground or other external reference for the counter electrode. The
key is that the counter electrode has a potential relative to the
spray site. As described in more detail herein below, counter
electrodes have been developed which are particularly suitable to
effecting a more uniform field about each spray site in a
substantially linear nozzle array.
[0037] Various EHD devices are known in the art, for example, U.S.
Pat. Nos. 6,302,331 to Dvorsky et al., 6,105,877, 6,457,470,
6,386,195, and 6,252,129 to Coffee, and 6,595,208 to Coffee et al.
Although, the various patents disclose different methods for
obtaining aerosols having an aerosol particle size of in the range
of from 0.1 um to 50 um, very little direction is provided
regarding suitable carrier liquids or improving spray site field
uniformity.
[0038] The term "aqueous liquid carrier vehicles" as used herein
refers to the liquid carrier vehicle in which the
biologically-active agent to be applied to a target surface is
dissolved or suspended. The aqueous liquid carrier vehicle is
required to contain at least about 60 weight percent to about 100
weight percent water, preferably from about 85 weight percent to
about 100 weight percent water, and more preferably from about 90
weight percent to about 100 weight percent water. The term "highly
aqueous" is used herein to describe aqueous liquid carrier vehicles
of the invention containing from about 90 weight percent to about
99 weight percent water and more preferably from about 95 weight
percent to about 100 weight percent water.
[0039] The aerosols of the invention can be used to deliver a
"biologically-active agent" to a target surface. The term "target
surface" as used herein may be any surface that benefits from
treatment of a biologically-active agent with a soft cloud of a
non-respirable aerosol according to the invention. As used herein,
the term "target surface" does not refer to an interior tissue
surface in a human or animal body such as the lungs or oral,
vaginal, or rectal cavities. The target surface may be for example,
plants, the soil (ground) around plants, the leaves and stems of
plants, the eyes, skin, coat, hide, or hide of animals such as
cats, dogs, and horses, the skin, eyes, and hair of humans, the
clothing of humans, and hard surfaces such as walls, floors,
tables, desks, beds, and other furnishings, manufacturing and
building infrastructure, and the like found in hospitals, nursing
homes, schools, and restaurants.
[0040] As used herein, the term "biologically-active agent" refers
to an agent or combination of agents that may be used in
agriculture, horticulture, veterinary medicine, personal animal, or
human care, disinfecting, and other applications where it is
desirable to deliver a biologically-active agent to a target
surface. The biologically-active agents contemplated for use in the
aerosols and methods of the invention include but are not limited
to herbicides, plant growth regulators, insecticides, fungicides,
miticides, biocides, antibacterials, antivirals,
anti-inflammatories, disinfectants, ocular decongestants, skin and
eye treatments, and the like.
[0041] Illustrative, but non-limiting examples of the aerosols
prepared as described herein are aerosols useful to deliver
insecticides and fungicides to trees and shrubs, plants such as
roses, orchids, violets, and other valuable flowering plants, as
well as to deliver herbicides to bed plantings and home gardens,
especially when handheld, battery powered, portable EHD devices are
used to produce the aerosol. The aerosols and methods of the
invention can be used to apply anti-tick, flea, and mite active
agents to the coat of mammals such as dogs, cats, and horses, the
skin and hair of humans, and the outer clothing of humans to
protect against fleas, ticks, and mites. The aerosols of the
invention can be used to apply disinfectant agents to hard surfaces
in schools, restaurants, hospitals, businesses, stores,
manufacturing facilities, and the home. In schools, for example,
the aerosols may be use to treat desks and cafeteria tables to
prevent the spread of viruses and bacterial, especially in
influenza season.
[0042] Illustrative, but non-limiting examples of specific
biologically-active agents useful in the aerosols and methods of
the invention include: herbicides e.g.,
(2,4,5-trichlorophenoxy)acetic acid,
(4-chloro-2-methylphenoxy)acetic acid, (2,4-dichlorophenoxy)acetic
acid, 4-(4-chloro-o-tolyloxy)butyric acid, fluazifop-p-butyl
(Ornamec.RTM., Gordon Corp, Kansas City, Mo.), pelargonic acid
(Scythe.RTM., Mycogen Corp., San Diego, Calif.), and isopropylamine
salt of N-(phosphonomethyl)glycine (Roundup.RTM., Scotts,
Marysville, Ohio or Glyphomax.RTM., Dow Agrosciences, Indianapolis,
Ind. ); fungicides e.g., manganese ethylene bisdithiocarbamate
(Maneb),
1-(4-chlorophenoxy)-3,3-dimethyl-1-(1H-1,2,4-triazol-1-yl)-2-butanone
(Strike.RTM., Olympic Horticultural Products, Mainland, Pa.),
azoxystrobin (Amistar.RTM., Syngenta, Basel, CH),
andtrifloxystrobin (Compass.TM., Bayer CropScience, Research
Triangle Park, N.C.); insecticides, e.g., Bacillus thuringiensis
(B.t.) (sold under the trade names Dipel.RTM. (Valent Corp, Dublin,
Calif.), Thuricide.RTM. (Bonide Products, Oriskany, N.Y.),
Bactospeine.RTM. (PBI/Gordon, Kansas City, Mo.), Leptox, Novabac,
and Bug Time); synthetic pyrethroids, e.g., permethrin,
cypermethrin, fenvalerate/esfenvalerate, tralomethrin, bifenthrin,
cyfluthrin, and lambda-cyhalothrin, O,O-Diethyl
0-(2-isopropyl-6-methyl-4-pyrimidinyl) phosphorothioate (diazinon);
treatments for fleas, ticks, and lice, e.g., lindane and malathion
(headlice, pubic lice), permethrin (ticks),
N,N-diethyl-meta-toluamide (DEET) (mosquitoes), fenthion, and
cythioate (fleas); and disinfectants, e.g., 3,4',5
tribromosalicylanilide (tribromsalan).
[0043] The biologically-active agents described herein are present
in the aerosols of the invention at a "biologically-effective
amount". As would be recognized by one skilled in the art, by
"biologically-effective amount" is meant an amount of a
biologically-active agent that is sufficient to provide the result
sought. In general, from about 0.01 weight percent to about 50
weight percent of the biologically-active agent will be present in
the liquid carrier vehicle. Specific details of the effective
dosage or concentration of a particular active agent may be found
in its product labeling, e.g., the package insert if the active
agent is regulated by the United States Food and Drug
Administration (FDA) (see, 21 CFR .sctn. 201.56 & 201.57) or
the labeling approved by the United States Environmental Protection
Agency (EPA) if the active agent is, e.g., a herbicide,
insecticide, miticide, and the like, which is covered by the rules
and regulations of the EPA.
[0044] When a biologically-active agent is added to the aqueous
liquid carrier vehicle, a solution is produced if the active agent
is soluble in the liquid carrier vehicle and a suspension is
produced if the active agent is insoluble. The term "suspension" as
used herein is given its ordinary meaning and refers to particles
of active agent or aggregates of particles of active agent
suspended in the liquid carrier vehicle. When the active agent is
present as a suspension the particles of active agent will
preferably be in the nano or micron range.
[0045] Among the advantages of the present invention is the ability
to use a highly-aqueous carrier liquid that is more "bio-friendly"
than conventional EHD carriers such as oil-based or solvent-based
carriers. The multi-nozzle configuration further enables higher
flowrates, while the counter electrodes of the present invention
enable design and control over particle size for a given
application. A further advantage in many applications is the
elimination of slippery or undesired oil or solvent residue from
other carrier liquids.
[0046] Depending on the biologically-active agent used in the
aerosols and methods of the invention, it may be advantageous to
include a co-solvent in the aqueous liquid carrier vehicle. The
co-solvent may be selected from such groups as alcohols, ethers,
alkyl sulfoxides, and propylene oxides. Examples of specific
co-solvents include ethanol, 2-ethylhexanol, diacetone alcohol,
diisobutyl ketone, isobutanol, isophorone, methyl isobutyl ketone,
n-butanol, n-pentanol, n-propanol, and combinations thereof.
Ethanol is a particularly preferred solvent because it is soluble
in water, is relatively inexpensive, and is safe for the
environment, animals, and humans.
[0047] The choice of a particular co-solvent or mixture of
co-solvents is within the skill of the art and will be made by the
skilled artisan taking into account such factors as how an aerosol
of the invention will be used, the particular active agent, and if
the target surface is a plant, animal, or hard surface. The
co-solvent should be soluble in or miscible with water, have a
viscosity in the range of 0.1 cPs to 100 cPs, and should not raise
the surface tension of the liquid carrier vehicle or aerosol above
60 dynes/cm. The co-solvent will be present in the liquid carrier
vehicle of the invention at from about zero weight percent to about
40 weight percent, preferably from about 1 weight percent to about
40 weight percent, and more preferably from about 5 weight percent
to about 15 weight percent.
[0048] An essential component of the highly-aqueous liquid carrier
vehicle of the invention and the aerosols produced therefrom is the
surfactant. It important that the surfactant selected be capable of
quickly lowering surface tension at the interface between air and
liquid as the liquid is exiting the EHD spray nozzle and the
electric charge is being applied to the liquid to form the aerosol
droplets.
[0049] While not being bound by theory, the choice of surfactant or
mixtures of surfactants used in the liquid carrier vehicles
described herein, it is important to control the surface tension as
the aerosol droplet is formed coming from the EHD spray nozzle. It
is desirable to keep the surface tension as low as possible at this
point in order to produced good aerosolization of the aqueous
liquid.
[0050] The surfactant, or mixtures of surfactants, used in the
aqueous liquid carrier vehicles of the invention should be
non-corrosive to the EHD device, should be environmentally safe at
the concentrations used, should be non-toxic to humans and animals
at the concentrations used, and should have no adverse effect on
the activity of the biologically-active agent being delivered in
the aerosols of he invention.
[0051] Examples of surfactants found to be useful in the aerosols
and liquid carrier vehicles of the invention are non-ionics such as
alkoxypoly(ethyleneoxy) alcohols such as Rhodasurf.RTM. BC 720
(Brenntag, Antwerp, BE), a water-soluble alkoxypoly(ethyleneoxy)
ethanol surfactant having an HLB (Hydrophile-Liphophile Balance) of
13.8, alkyl polyglycosides sold under the tradenames Agnique.RTM.
PG 8107-U (HLB 13.6) and Agnique.RTM. PG 9116 (HLB 13.1) (both from
Cognis Corp., Cincinnati, Ohio); polyoxyethylene ethers, e.g.,
polyoxyethylene(10) tridecyl ether (ANAPOE.RTM.-C.sub.12E.sub.10,
Anatrace, Maumee, Ohio); alkyl-.beta.-D-glucopyranosides, e.g.,
hexyl-, heptyl-, octyl-, decyl-, and
dodecyl-.beta.-D-glucopyranoside; and
alkyl-.beta.-D-maltoglucopyranosides, e.g., hexyl-, octyl-, nonyl-,
decyl-, undecyl-, dodecyl-, and
tetradecyl-.beta.-D-maltoglucopyranoside (Anatrace).
[0052] The choice of a particular surfactant for use in a
particular liquid carrier vehicle will be made considering the
physical and chemical properties of the active agent to be
aerosolized, e.g. whether the active agent is soluble in water or
very insoluble, the amount of co-solvent in the liquid carrier
vehicle, the nature and amount of any excipient in the liquid
carrier vehicle, the desired particle size of the resulting aerosol
and the desired spray flow rate. The surfactant will be present in
the liquid carrier vehicle of the invention at from about 0.05
weight percent to about 10 weight percent, preferably from about
0.05 weight percent to about 5 weight percent, and more preferably
from about 0.1 weight percent to about 2.5 weight percent.
[0053] Other optionally-present components in the aerosols and
aqueous liquid carrier vehicles of the invention are
"biologically-acceptable excipients". A used herein, the term
"biologically-acceptable excipients" include those compounds and
additives listed by the FDA as being generally recognized as safe
(GRAS) for use in humans (see, 21 CFR .sctn. 182). The term also
includes those additives that are exempted from the requirement of
a tolerance when used in accordance with good agricultural
practices. See Federal Insecticide, Fungicide and Rodenticide Act
(FIFRA), 7 U.S.C. .sctn.136 et seq. (1996) and 40 C.F.R. .sctn.
180.1001.
[0054] Illustrative of such excipients include but not limited to
polyols e.g., propylene glycol, glycerol, polyvinyl alcohol (PVA),
and polyethylene glycol (PEG) having an average molecular weight
between about 200 and 4000, antioxidants, e.g., Vitamin E, Vitamin
E TPGS (alpha-tocopferol polyethylene glycol 1000 succinate),
ascorbic acid, anti-microbials, e.g., parabens, pH-adjusting
agents, e.g., sodium hydroxide and hydrochloric acid,
viscosity-adjusting agents, e.g., polyvinylpyrrolidone, and ionic
materials to add charge to the liquid carrier formulation are
contemplated for use herein.
[0055] The aerosols and aqueous liquid carrier vehicles of the
invention may include minor amounts, that is, up to 10 weight
percent, preferably from about 0.05 weight percent to about 5
weight percent, and more preferably from about 0.1 weight percent
to about 2.5 weight percent of a "biologically-acceptable
excipient". As used herein, the term "biologically-acceptable
excipient" refers not only to a single excipient but also to
mixtures of two or more excipients; e.g., an aerosol or aqueous
liquid carrier vehicle of the invention might contain an
antioxidant, a viscosity-adjusting agent, and an ionic
material.
[0056] While the selection of any particular
biologically-acceptable excipient or mixture of excipients is
within the skill of the art, the decision regarding whether to add
an excipient, and if so which one, will be made taking into account
the purpose of the excipient in a specific aqueous liquid carrier
vehicle. Any excipient used in the aerosols or liquid carrier
vehicles described herein should have no effect or minimal effect
on the sprayability of the aqueous liquid containing the
biologically-active agent.
[0057] The particle size of the aerosol droplets of the invention
should be sufficiently large to ensure that the aerosol particles
will not be inhaled by an animal or human. The particle size of the
aerosol droplets should average from about 60 .mu.m to about 800
.mu.m, preferably from about 80 .mu.m to about 500 .mu.m, and more
preferably about 150 .mu.m to about 350 .mu.m in diameter. The
average particle size of the droplets is usually referred to as
"mass median diameter" (MMD). It is also important that the
corresponding geometric standard deviation (GSD) be low, indicating
a monodisperse or nearly monodisperse aerosol. A polydisperse
aerosol will contain many aerosol particles that are smaller than
the target range and many that are larger. Aerosol particles
smaller than about 50 .mu.m might be inhaled or "respired" by
animals or humans as the aerosol is being applied to the target
surface. On the other hand, if the aerosol particles are larger
than about 800 .mu.m the aerosol droplets can coalesce and drip off
the target surface wasting the biologically-active agent. It is
thus highly desirable that the aerosol be as nearly monodisperse as
possible.
[0058] The highly-aqueous liquid carrier vehicles and compositions
prepared according to the invention have a resistivity of from
about 0.05 ohm-m to about 100 ohm-m, preferably from about 0.1
ohm-m to about 10 ohm-m, and more preferably from about 0.25 ohm-m
to about 5 ohm-m. The highly-aqueous liquid carrier vehicles and
compositions prepared according to the invention have a viscosity
of from about 0.1 cPs to about 100 cPs, and a surface tension of
from about 20 dynes/cm to about 60 dynes/cm.
[0059] Unlike the prior art aqueous liquid carrier vehicles, which
are generally aerosolized/ sprayed at relatively low flow rates (on
the order of .mu.l/sec), the highly-aqueous liquid carrier vehicle
of the invention maybe sprayed at commercially-acceptable flow
rates. As an example, if a multiple site nozzle having ten sites is
used to produce an aerosol according to the invention, and the
flowrate at each site is on the order of 0.5 .mu.l/sec/site to 2.0
.mu.l/sec/site, an overall flow rate of 5 .mu.l/sec to 20 .mu.l/sec
would result.
[0060] The following examples illustrate the method and various
compositions and carrier vehicles described herein. The examples
were aerosolized using a linear nozzle assembly (4 metallic nozzle
ports plus a "dummy" nozzle at each end) with curvilinear-shaped
grounded counter electrodes. The nozzles were constructed of
stainless steel tubing, had an outside diameter of 0.8 mm, an
inside diameter of approximately 0.5 mm and were on 3.5 mm centers.
The counter electrodes were constructed of 0.8 mm tubing and, when
installed, measured 12.7 mm from top-of-arc to top-of-arc. Each arc
was 15.9 mm start-of-bend to end-of-bend. Each arc was orthogonal
to the nozzles and was positioned at various points behind, even
with, or in front of the tops of the nozzles.
[0061] In the examples below, the term "kV" indicates the voltage
applied to each spray site of the nozzle of the EHD device to place
a charge on the composition. A high voltage source ranging from 0
to +20 kV and 0 to -20 kV was used. The particle size analysis was
performed using a Malvern MasterSizer.RTM. X particle size analyzer
(Malvern Instruments, Inc., Southborough, Mass.). It has been
discovered, furthermore, that a charge of negative polarity may
work best for spraying highly aqueous formulations, due, it is
thought to the bipolar nature of the water molecule.
[0062] In general, the formulations of the invention are prepared
by adding the components together and mixing to give a liquid
solution, an emulsion, or solid in liquid suspension. If the active
agent is soluble in water, the active agent is mixed with the
aqueous liquid and the co-solvent, surfactant, and excipient (if
any) are added to the aqueous solution and the mixture is shaken or
stirred to produce a homogenous solution. Where the active agent is
substantially insoluble in the aqueous liquid component of the
carrier vehicle and is soluble in the co-solvent, the active agent
is added to the co-solvent, mixed, and the mixture is added to the
aqueous component of the aqueous carrier vehicle. Where the active
agent is only slightly soluble in water and/or the co-solvent, it
may be advantageous to disperse fine particles of the active agent
in the liquid carrier vehicle in order to achieve the desired
concentration of the active in the carrier vehicle.
TABLE-US-00001 Reagents Ortho Weed-B-Gon .RTM. (Solaris Group,
Monsanto Co., San Ramon, CA) 2,4-D [2,4-dichlorophenoxy acetic
acid] 3.05 wt % MCPP [2-(4-chloro-2-methylphenoxy) propionic acid]
10.6 wt % Dicamba [3,6-dichloro-2-methoxy benzoic acid] 1.30 wt %
Inerts 85.05 wt % C-9 [n-nonyl-.beta.-D-glucopyranoside] C-10
[n-decyl-.beta.-D-glucopyranoside] Saline [phosphate-buffered
saline] Emulphogene .RTM. (Sigma-Aldrich, St. Louis, MO)
[polyoxyethylene-10-tridecyl ether] EtOH [ethanol] Agnique .RTM. PG
8107-G (Cognis, Cincinnati, OH) [C.sub.8-C.sub.10 alkyl
polyglucoside] Agnique .RTM. PG 9116 (Cognis, Cincinnati, OH)
[C.sub.9-C.sub.11 alkyl polyglucoside] PBS [phosphate buffer
solution] phosphate 10 mM NaCl 150 mM Desonic .RTM. DA-4 (Chemtura,
Middlebury, CT) [ethoxylated iso-decyl alcohol]
EXAMPLE 1
TABLE-US-00002 [0063] Composition (wt %) Weed-B-Gon .RTM. 10.90
EtOH 22.35 H.sub.2O 65.75 C-10 1.00 Resistivity (ohm-m) 1.59
Surface Tension (dynes/cm) 36.9 Viscosity (cPs) ND Flowrate
(.mu.l/sec/site) 1.04 Mass Median Diameter 107 (MMD) (.mu.m)
Geometric Standard 1.18 Deviation (GSD) Nozzle Configuration
Four-nozzle linear array with an additional "dummy" electrode at
each end and linear parallel ground electrodes. Voltage (kV) -8.2
Particle Size Data FIG. 1
[0064] As shown by Ex. 1 and accompanying FIG. 1, no particle sizes
less than 60 .mu.m were produced. Satisfactory results were also
obtained at flowrates of 0.52 and 0.625 .mu.l/sec/site. MMDs of up
to 376 .mu.m with a GSD of 1.29 were observed. Samples with lower
concentrations of EtOH (3 weight percent and 6 weight percent) did
not spray well and were not analyzed for MMD and GSD.
EXAMPLE 2
TABLE-US-00003 [0065] Composition (wt %) Weed-B-Gon .RTM. 99 C-10 1
Resistivity (ohm-m) 0.485 Surface Tension (dynes/cm) 39.3 Viscosity
(cPs) 1.96 Flowrate (.mu.l/sec/site) 1.25 MMD (.mu.m) 320 GSD 1.22
Nozzle Configuration Four-nozzle linear array with an additional
"dummy" electrode at each end and curvilinear ground electrodes.
Voltage (kV) +9.2 Particle Size Data FIG. 2
[0066] As shown by Ex. 2 and accompanying FIG. 2, less than two
percent of the particles were less than 60 .mu.m. Satisfactory
results were also obtained at flowrates of 0.625, 1.375, and 2.75
.mu.l/sec/site.
EXAMPLE 3
TABLE-US-00004 [0067] Composition (wt %) Weed-B-Gon .RTM. 100
Resistivity (ohm-m) 0.46 Surface Tension (dynes/cm) 41.9 Viscosity
(cPs) 1.86 Flowrate (.mu.l/sec/site) 1.375 MMD (.mu.m) ND GSD ND
Nozzle Configuration Four-nozzle linear array with an additional
"dummy" electrode at each end and curvilinear ground electrodes.
Voltage (kV) +8.5 and +9.0 Particle Size Data ND
[0068] Although satisfactory sprays were obtained, they were less
satisfactory than those observed when a surfactant was added.
EXAMPLE 4
TABLE-US-00005 [0069] Composition (wt %) Weed-B-Gon .RTM. 99
Agnique PG 9116 .RTM. 1 Resistivity (ohm-m) 0.49 Surface Tension
(dynes/cm) 33.8 Viscosity (cPs) 1.86 Flowrate (.mu.l/sec/site) 1.04
MMD (.mu.m) 190 GSD 1.37 Nozzle Configuration Four-nozzle linear
array with an additional "dummy" electrode at each end and
curvilinear ground electrodes. Voltage (kV) +8.9 Particle Size Data
FIG. 3
[0070] As shown by Ex. 4 and accompanying FIG. 3, about two percent
of the particles were less than 80 .mu.m. Satisfactory results were
also obtained at flowrates of 2.1 and 3.125 .mu.l/sec/site.
EXAMPLE 5
TABLE-US-00006 [0071] Composition (wt %) PBS 99 C-10 1 Resistivity
(ohm-m) 0.67 Surface Tension (dynes/cm) 29.1 Viscosity (cPs) 1.00
Flowrate (.mu.l/sec/site) 0.83 MMD (.mu.m) 156 GSD 1.14 Nozzle
Configuration Four-nozzle linear array with an additional "dummy"
electrode at each end and curvilinear ground electrodes. Voltage
(kV) +8.6 Particle Size Data FIG. 4
[0072] As shown by Ex. 5 and accompanying FIG. 4, no particle sizes
less than 60 .mu.m were produced. Both linear parallel and
curvilinear ground electrodes gave satisfactory sprays.
Satisfactory results were also obtained at flowrates of 0.42, 1.04,
and 2.08 .mu.l/sec/site.
EXAMPLE 6
TABLE-US-00007 [0073] Composition (wt %) PBS 100 Resistivity
(ohm-m) 0.6 Surface Tension (dynes/cm) 67.8 Viscosity (cPs) 1.16
Flowrate (.mu.l/sec/site) ND MMD (.mu.m) ND GSD ND Nozzle
Configuration Formulation could not be sprayed using any
configuration. Voltage (kV) NA Particle Size Data ND
[0074] Ex. 6 seems to indicate a surfactant is needed to spray
PBS.
EXAMPLE 7
TABLE-US-00008 [0075] Composition (wt %) DMA salts of 2,4-D 3.05
MCPP 10.6 Dicamba 1.30 The above were dissolved in PBS and one
percent C-10. Resistivity (ohm-m) 0.38 Surface Tension (dynes/cm)
37.5 Viscosity (cPs) 1.71 Flowrate (.mu.l/sec/site) 1.04 MMD
(.mu.m) ND GSD ND Nozzle Configuration Four-nozzle linear array
with an additional "dummy" electrode at each end and curvilinear
ground electrodes. Voltage (kV) +9 Particle Size Data ND
[0076] At flowrates of 0.42 and 1.04 .mu.l/sec/site, a reasonably
good spray was produced.
EXAMPLE 8
TABLE-US-00009 [0077] Composition (wt %) DMA salts of 2,4-D 3.05
MCPP 10.6 Dicamba 1.30 The above were dissolved in water with one
percent C-10. Resistivity (ohm-m) 0.54 Surface Tension (dynes/cm)
36.8 Viscosity (cPs) 1.66 Flowrate (.mu.m/sec/site) 0.42 MMD
(.mu.m) 187 GSD 1.16 Nozzle Configuration Four-nozzle linear array
with an additional "dummy" electrode at each end and curvilinear
ground electrodes. Voltage (kV) +9.8 Particle Size Data FIG. 5
[0078] As shown by Ex. 8 and accompanying FIG. 5, about 20 percent
of the particles were less than 80 .mu.m. Good sprays were also
obtained at 1.04 .mu.l/sec/site. At higher flowrates, above 2
.mu.l/sec/site, only jets were obtained with inconsistent
sprays.
EXAMPLE 9
TABLE-US-00010 [0079] Composition (wt %) Weed-B-Gon .RTM. 99
Emulphogene .RTM. 1 Resistivity (ohm-m) 0.47 Surface Tension
(dynes/cm) 38.0 Viscosity (cPs) 1.68 Flowrate (.mu.l/sec/site) 1.04
MMD (.mu.m) 179 GSD 1.28 Nozzle Configuration Four-nozzle linear
array with an additional "dummy" electrode at each end and
curvilinear ground electrodes. Voltage (kV) +9.7 Particle Size Data
FIG. 6
[0080] As shown by Ex. 9 and accompanying FIG. 6, about 11 percent
of the particles were less than 80 .mu.m. Good sprays were also
obtained at 0.42 and 1.25 .mu.l/sec/site. At flowrates of 2.5
.mu.l/sec/site and above, arcing and inconsistent sprays
resulted.
EXAMPLE 10
TABLE-US-00011 [0081] Composition (wt %) Weed-B-Gon .RTM. 99.9 C-10
0.1 Resistivity (ohm-m) 0.44 Surface Tension (dynes/cm) 42.2
Viscosity (cPs) 1.65 Flowrate (.mu.l/sec/site) 0.83 MMD (.mu.m) 175
GSD 1.12 Nozzle Configuration Four-nozzle linear array with an
additional "dummy" electrode at each end and curvilinear ground
electrodes. Voltage (kV) +8.7 Particle Size Data FIG. 7
[0082] As shown by Ex. 10 and accompanying FIG. 7, good sprays are
possible with lower concentrations of the C-10 surfactant. Good
sprays were also observed at 0.42, 1.25, and 2.5 .mu.l/sec/site,
however, higher flowrates (above 3 .mu.l/sec/site) did not yield
consistent sprays and only jets were observed.
EXAMPLE 11
TABLE-US-00012 [0083] Composition (wt %) Weed-B-Gon .RTM. 99
Agnique PG 8107 .RTM. 0.9 C-10 0.1 Resistivity (ohm-m) 0.45 Surface
Tension (dynes/cm) 36.6 Viscosity (cPs) 1.73 Flowrate
(.mu.l/sec/site) 0.83 MMD (.mu.m) 250 GSD 1.61 Nozzle Configuration
Four-nozzle linear array with an additional "dummy" electrode at
each end and curvilinear ground electrodes. Voltage (kV) +9
Particle Size Data FIG. 8
[0084] Ex. 11 demonstrates the feasibility of using a combination
of two different surfactants for spraying aqueous formulations
using EHD. Good sprays were also observed at 0.42 and 0.84
.mu.l/sec/site. As shown in FIG. 8, about two percent of the
particles were less than 60 .mu.m.
[0085] EXAMPLE 12
TABLE-US-00013 Composition (wt %) Weed-B-Gon .RTM. 99 Desonic DA-4
1 Resistivity (ohm-m) 0.46 Surface Tension (dynes/cm) 35.5
Viscosity (cPs) 1.73 Flowrate (.mu.l/sec/site) 1.25 MMD (.mu.m) 134
GSD 1.41 Nozzle Configuration Four-nozzle linear array with an
additional "dummy" electrode at each end and curvilinear ground
electrodes. Voltage (kV) +9.7 Particle Size Data FIG. 9
[0086] As shown by Ex. 12 and accompanying FIG. 9, good sprays were
observed with this formulation. As shown in FIG. 9, less than 15
percent of the particles were below 60 .mu.m. A flowrate of 0.42
was also successful in producing satisfactory sprays.
[0087] Referring now to FIGS. 10-12, in an EHD nozzle assembly 10
comprising a substantially linear array 12 of individual nozzles
14, it has been found that the nominal central-most spray sites 16
exhibit instability during spraying, especially as the number of
nozzles 14 increases. The charge associated with each spray site 14
is affected by the charge associated with nearby spray sites. Thus,
the spray sites in the central portion 16 of the array 12 are more
affected by nearby spray sites than those in the outer portions 18.
As will be appreciated by one skilled in the art, a multi-nozzle
array may not be required and a single nozzle 14 may comprise the
central-most spray site 16. Additionally, depending upon the charge
configuration, as well as other factors, the spray sites
denominated "central" 16 and "outer" 18 may change. One or more
linear field-equalizing counter electrodes (not shown) have the
effect of equalizing the field of the entire array of spray sites.
In practice, however, it has been found that the central spray
sites 16, being most affected by adjacent nozzles 14, require,
relative to the charge of that spray site, a more intense counter
charge. This may be effected by exposing the central sites 16 to a
more intense field than the outer sites 18. As shown in FIGS.
10-12, this may be accomplished by decreasing the distance between
the central spray sites 16 and one or more counter electrodes 22,
24 with a curvilinear counter electrode. As will be appreciated by
those skilled in the art, various configurations are potentially
effective. The counter electrode 22, 24 may be orthogonal, as shown
as solid lines in FIG. 11, or non-orthogonal, as shown as dashed
lines in FIG. 11, to the nozzles 12. Further, the field-equalizing
effect may be brought about by numerous means. As seen in FIGS.
13-15, a counter electrode 42, 44 may comprise a surface 43, 45
with edges 46, 47 in various configurations relative to the spray
sites 14. As shown in FIGS. 16-18, the counter electrode 62, 64 may
comprise one or more elements 65 positioned parallel to the nozzles
12. Such a configuration may be further adapted to provide selected
charges, or ground, on the individual counter electrode elements 65
as desired. As will be appreciated by one skilled in the art, the
counter electrode elements 65 (shown in linear relationship)
closest to the central sites 16 may be moved laterally closer (not
shown) or may have a different charge to effect the desired
countering effect. Finally, FIGS. 19-21 illustrate another
embodiment of a nozzle assembly according to the present invention.
To properly establish a more equal field at the central nozzles 16,
the nozzle arrays 13, 15 may be configured in a curvilinear
geometry with the counter electrode 72 positioned proximate.
[0088] As well, a curvilinear array of nozzles may be combined with
curvilinear counter electrodes or a curvilinear arrangement of
counter electrode elements to achieve more uniform spraying in a
desired spray pattern.
[0089] As will be appreciated by those skilled in the art, a myriad
of configurations are possible within the spirit of the invention.
By adjusting the field of the spray sites with one or more counter
electrodes, spray site uniformity may be improved with commensurate
improvement in particle size uniformity at increased fluid flow and
increased rates of aerosol delivery.
[0090] Turning now to FIGS. 22-51, a series of finite element
analyses (FEA) were conducted on electric fields associated with a
linear array of spray port counter electrodes similar to those
discussed above in reference to FIGS. 10-12. As in FIGS. 10-12, one
or more "dummy" electrodes 20 are placed at each end of the nozzle
array 12 and are not supplied with fluid. The dummy electrodes 20
serve to direct the aerosol generated from the array 12 and
eliminate the large electric field variation at the outer sites 18
relative to the central sites 16. The analyses were performed with
Maxwell.RTM. (Ansoft Corp., Pittsburgh, Pa.), and the models are
two-dimensional. The cases discussed below present the parameters
associated with the geometry, a plot of the electric field
magnitude associated with the geometry, and a graph of the electric
field around half of the spray sites 14. Because of symmetry in the
models, detail of only half of the sites needs to be presented. Two
counter electrodes (nominally 142, 144) are shown above and below
the linear array of spray sites 12. Optionally, one counter
electrode 142 could be used in the actual nozzle design. The actual
nozzle array 12, the spray sites 14, and the counter electrode 142,
144 are in the same plane. These analyses examine the relationships
of relative spacings and the shapes of reference electrodes that
would produce the most uniform electric field at each spray site
14. Ideally, if the electric field is the same at each port, the
formation of the Taylor cone and the aerosol generation will also
be uniform. In turn, the droplet or particle size distribution will
also be uniform and narrow in its dispersion of sizes.
[0091] Table 1, below, summarizes the cases.
TABLE-US-00014 TABLE 1 Center-to-Center Center-to-Edge Radius Into
Array Case Sites (mm) (mm) (mm) (mm) 1 4 5 10 N/A N/A 2 4 5 20 N/A
N/A 3 4 10 10 N/A N/A 4 4 10 20 N/A N/A 5 4 15 10 N/A N/A 6 4 10 20
80 N/A 7 4 10 20 40 N/A 8 4 10 20 25 N/A 9 10 10 20 N/A N/A 10 10
10 20 40 20 11 10 10 30 60 30 12 10 10 30 30 30 13 10 10 30 2.5 7.5
14 10 10 30 2.5 12.5 15 10 10 20 2.5 5
[0092] In Table 1, the sites noted are active sites. In all cases,
the active sites were flanked by one dummy electrode at each end.
The Center-to-Edge dimension is the distance from the center of the
port (spray site) to the edge of the counter electrode.
[0093] In each case, the nozzle ports 14, have an outside diameter
(O.D.) of 2 mm which is a median size for many practical ports.
Also in each case, because it can be difficult to accurately
examine the field directly at the surface of the spray port, an
arbitrary circle 0.5 mm beyond the periphery of the port was
established to measure and plot the field about each port. Finally,
in addition to the sites noted, there is an additional dummy port
20 at each end. (See, e.g., FIG. 22.)
[0094] In the detail shown in each case (e.g., FIG. 23), only half
of the ports 14, 20 are shown. By adjusting the relationships of
relative spacings and the shapes of the counter electrodes, the
most uniform field for each port 14 is sought. Of course, the field
of the dummy electrode 20 is not relevant. If the field is the same
for each port 14 is similar, the formation of the Taylor cone and
the aerosol generation will also tend toward uniformity. In turn,
the droplet or particle size distribution will also tend toward
uniformity and the dispersion will be more narrow.
[0095] Seen in FIGS. 22 and 23, Case 1 is the most basic of nozzle
configurations. In Case 1, the counter electrodes 142, 144 are
twice the port-to-port (center-to-center) spacing from the array
12, linear and parallel to the array 12. Shown in FIG. 23 are the
differences in the fields between port 102 and port 103. The reason
for a dummy port 101 can be seen in FIG. 20. The differences in the
fields of the sites 102, 103 are significant and could cause
variations in the aerosol particle size produced.
[0096] Case 2, shown in FIGS. 24 and 25, illustrates the effect of
positioning the counter electrodes (not shown) at four times the
port-to-port spacing from the array 12. As shown in FIG. 25, the
variations between the sites 102, 103 have increased when compared
with Case 1.
[0097] Case 3, shown in FIGS. 26 and 27, illustrates the effect of
positioning the counter electrodes 142, 143 at the same distance
from the linear array 12 as the port-to-port spacing. As shown in
FIG. 27, the variations between the sites 102, 103 have improved,
but still larger than preferred.
[0098] Case 4, shown in FIGS. 28 and 29, illustrates the effect of
positioning the counter electrodes 142, 143 at 20 mm, or twice the
port-to-port distance of 10 mm. The field disparity has increased
from Case 3.
[0099] Case 5, shown in FIGS. 30 and 31, illustrates the effect of
positioning the counter electrodes 142, 143 at 10 mm, or closer
than the adjacent sites 102, 103. This takes relative spacing to
the extreme. From FIG. 31, it appears that the sites are beginning
to look like independent entities. That is, the field effect from
adjacent sites is much less than that of the counter electrodes
142, 143. As a result, as seen in FIG. 31, the fields at the sites
102, 103 appear to be nearly identical.
[0100] Case 6, shown in FIGS. 32 and 33, is the first model
designed to examine the effect of curved counter electrodes 142,
143. The model maintains its symmetry and the minimum counter
electrode-site spacing occurs at the midpoint of the linear array
12. For practical purposes, the minimum counter electrode-site
spacing was set to twice the site-to-site spacing. This ratio would
be adjusted in actual applications.
[0101] Case 7, shown in FIGS. 34 and 35, illustrates that further
reduction in the radius of the counter electrodes 142, 143, further
improvement in uniformity results.
[0102] Case 8, shown in FIGS. 33 and 34, illustrates the effect of
further reduction in the radius of the counter electrodes 142, 143.
The disparity in the field increases at a different location around
the spray sites 103, 103. (Compare with Case 7.)
[0103] Case 9, shown in FIGS. 38 and 39, is the first model
designed to examine a more complex linear array 12. As seen in FIG.
35, there are ten active sites 14 plus two dummy electrodes 20. In
FIG. 39, the field magnitude is not studied for the dummy site 20
since it has no liquid and, thus, no Taylor cone. The sites closer
to the middle of the array 12, the so-called inner sites 16
experience similar conditions and, therefore, exhibit similar
fields. The sites at the outermost positions of the array 12, the
so-called outer sites 18 experience more edge effects. Thus, the
fields around the outer sites 18 are increasingly disparate from
the inner sites 16. Note, again, as will be appreciated by one
skilled in the art, that the designation of sites in the array 12
as inner 16 and outer 18 is somewhat arbitrary and is provided as a
convenience for analysis and discussion only.
[0104] Case 10, shown in FIGS. 40 and 41, illustrates further
development in the concept of using counter electrodes 142, 143 to
balance the fields around each site 14. Since the inner sites 16 of
the array 12 exhibit substantial uniformity, there was no
alteration of the counter electrode-spray site geometry. However,
based upon Case 9, the intensity of the field around the outer
sites 18 have room for improvement. As seen in FIG. 38, there is
significant improvement to the uniformity of all sites.
Importantly, the counter electrodes 142, 144 begin to curve away
from the array 12 at a point "inboard" from the outermost nozzles,
especially the active nozzles.
[0105] Case 11, shown in FIGS. 42 and 43, illustrates the effect of
beginning the radius of curvature of the counter electrodes 142,
143 further inboard from the dummy ports 20. As seen in FIG. 43,
the field intensities for all but the most outboard site are very
similar. As with Case 10, the counter electrodes 142, 144 begin to
curve away from the array 12 at a point "inboard" from the
outermost nozzles.
[0106] Case 12, shown in FIGS. 44 and 45, illustrates the effect of
further increasing the radius of curvature of the counter
electrodes 142, 143. While some improvement is made to the outer
sites 18, the disparity of the other, inner sites 16, has
increased. As with Case 10, the counter electrodes 142, 144 begin
to curve away from the array 12 at a point "inboard" from the
outermost nozzles.
[0107] Case 13, shown in FIGS. 46 and 47, illustrates the effect of
reducing the curvature of the counter electrode 142, 143 to
rounding the edges of the electrode itself. In Case 13, the counter
electrodes 142, 144 are defined as flat and having a thickness of 5
mm and ends that are rounded to the thickness diameter of 5 mm. The
rounding shown in FIG. 46 helps prevent a high field intensity on
the edge of the counter electrode 142, 143. This may also be
accomplished, for example, by adding a "bead" to each end or using
sheet metal for the counter electrodes 142, 143, and rolling the
end over. As with Cases 10-12, the end of the counter electrodes
142, 144 is positioned inboard of the outer nozzles.
[0108] Case 14, shown in FIGS. 48 and 49, illustrates the effect of
reducing the length of the counter electrodes 143, 142 relative to
the array 12. As seen in FIG. 49, there are diminishing returns to
this geometry modification.
[0109] Case 15, shown in FIGS. 50 and 51, illustrate a desirable
result; the fields of all spray sites 14 are nearly identical. In
relative terms, it was found that the most effective geometry is
one where the spacing between the counter electrodes 142, 143 and
the array 12 is twice the spacing between the individual sites 14.
The ends of the counter electrodes 142, 143 are located midway
between the dummy electrode 20 and the first active spray site.
[0110] One skilled in the art will readily appreciate that the
present invention is well adapted to carry out the objects and
obtain the ends and advantages mentioned, as well as those objects,
ends, and advantages inherent herein. The present examples, along
with the methods, procedures, treatments, specific active agents,
and devices described herein, are presently representative of
preferred embodiments, are exemplary, and are not intended as
limitations on the scope of the invention. Changes therein and
other uses will occur to those skilled in the art which are
encompassed within the spirit of the invention as defined by the
scope of the claims.
* * * * *